Genital herpes is one of the most prevalent sexually transmitted infections (STI) worldwide and is associated with substantial morbidity. The impact of genital herpes as a public health threat is amplified because of its epidemiologic synergy with HIV. Epidemiological studies consistently demonstrate that genital herpes infection increases the risk of HIV transmission and acquisition. The increasing prevalence of genital herpes, the frequent recurrence of clinical episodes, the high frequency of asymptomatic shedding and the association of HSV with HIV transmission highlight the urgent need for control measures in populations at risk for both viruses. One preventative strategy is the development of topical microbicides, self-administered agents designed for vaginal use to prevent STI. Goals for the development of topical microbicides are that they be safe, affordable, effective against HIV, HSV, and other STI, and stable in the presence of genital tract secretions. A key component to the pre-clinical development of topical microbicides is evaluation of safety and efficacy in small animal models that reflect human disease. Most animal studies for genital herpes have been conducted using either a murine or guinea pig model. However both of these have significant limitations. We recently found that the cotton rat, a common New World rodent in a family distinct from the laboratory mouse and rat, provides a potentially biologically superior model of human genital disease. Salient features of this model are that vaginal infection does not require hormonal manipulation, animals recover from primary infection but are prone to spontaneous clinical recurrences that mimic human disease, and infection is prevented by pretreatment with a candidate topical microbicide, PRO2000. Additional advantages include the availability of reagents to study the mucosal response to HSV and to microbicides, ability to induce reactivation experimentally with dexamethasone, the potential to study vertical and horizontal transmission, and the possibility of developing the cotton rat as a model of co-infection with other STI. Therefore, the goal of Phase I of this STTR application is to optimize the cotton rat as a model to evaluate the effectiveness and safety of topical microbicides to prevent sexual or perinatal transmission of HSV. The specific aims to achieve this goal are: (i) Evaluate the cotton rat as a model of genital herpes infection reflective of human disease. The hypothesis to be tested is that the cotton rat will serve as a model to study primary herpes infection, clinical and asymptomatic recurrences, and horizontal (female-to-male or male-to-female) and vertical (intra-partum mother-to-offspring) transmission; (ii) Determine whether the cotton rat will provide a surrogate marker of microbicide effectiveness against HSV and safety. A major gap in the preclinical development of vaginal microbicides is the absence of surrogate markers to predict both efficacy and safety of vaginal microbicides. We hypothesize that the cotton rat will fill this niche. Genital herpes infection is one of the most prevalent sexually transmitted infections and is a major co-factor in the HIV/AIDS epidemic. Novel strategies to prevent transmission and acquisition of both pathogens, such as the development of safe and effective vaginal microbicides, are urgently needed. A major limitation in the development of this novel class of drugs is the absence of a small animal model to predict safety and effectiveness. Preliminary studies indicate that the cotton rat will fill this niche. The goal of Phase I of this STTR application is to optimize the cotton rat as a model to evaluate the effectiveness and safety of topical microbicides to prevent sexual or prenatal transmission of HSV. [unreadable] [unreadable] [unreadable]